This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ/cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

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Cellular distribution and functions of P2 receptor subtypes in different systems.

Publisher Summary This chapter discusses the physiological role of adenosine in the central nervous system (CNS). In particular, the chapter's attention is directed to the actions of adenosine and related purines in the CNS. One of the major advances in the understanding of purine actions in the central nervous system is the characterization of high affinity specific receptors for purines in brain membranes. The physiological actions of purines, the receptors and biochemical actions that underlie these functional responses and behavioral responses to purinergic drugs are considered. There are three different adenosine receptor sites in brain, which can be distinguished primarily by their effects upon adenylate cyclase, their pharmacological properties, and by their ability to bind labeled analogs of adenosine. One of the best-characterized physiological actions of adenosine is the inhibition of the release of neurotransmitters, an action that has been unequivocally established at many peripheral synapses. If one thing remains clear, it is that purines have a multitude of complex actions at every level, including the biochemical, physiological, and behavioral. There remains little question, but that adenosine or other purines constitute important and rather ubiquitous regulators of neuronalactivity in brain. Despite the evidence that purines play a significant role in neural function, it has remained difficult to define the functional role(s) of purines in brain.

The physiological role of adenosine in the central nervous system.

Modulation of neurotransmission by purine nucleotides and nucleosides.

There is mounting evidence that the established paradigm of nitric oxide (NO) biochemistry, from formation through NO synthases, over interaction with soluble guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part of a richer chemistry through which NO elicits biological signaling. Additional pathways have been suggested that include interaction of NO-derived metabolites with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls. Despite the overwhelming attention paid in this regard to RSNOs, little is known about the stability of these species, their significance outside the circulation, and whether other nitros(yl)ation products are of equal importance. We here show that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S-nitrosation in vivo and that the products of these reactions are constitutively present throughout the organ system. Our study further reveals that all NO-derived products are highly dynamic, have fairly short lifetimes, and are linked to tissue oxygenation and redox state. Experimental evidence further suggests that nitroso formation occurs substantially by means of oxidative nitrosylation rather than NO autoxidation, explaining why S-nitrosation can compete effectively with nitrosylation. Moreover, tissue nitrite can serve as a significant extravascular pool of NO during brief periods of hypoxia, and tissue nitrate/nitrite ratios can serve as indicators of the balance between local oxidative and nitrosative stress. These findings vastly expand our understanding of the fate of NO in vivo and provide a framework for further exploration of the significance of nitrosative events in redox sensing and signaling. The findings also raise the intriguing possibility that N-nitrosation is directly involved in the modulation of protein function.

https://www.pnas.org/content/pnas/101/12/4308.full.pdf

Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo.

1 The effects of adenosine and various derivatives were examined in the in vitro hippocampal slice preparation from rat

2 The amplitudes of extracellularly recorded field potentials from the CA1 region were depressed by adenosine, and this effect could be antagonized by methylxanthines Because presynaptic field potentials were unaffected by adenosine, while the field epsp was depressed, adenosine would appear to act at a synaptic site to depress transmission

3 Adenosine deaminase, which breaks down adenosine to inosine, increased the amplitude of synaptic responses, while hexobendine, which blocks reuptake of adenosine, had a depressant effect This strongly suggests that the endogenous release of adenosine from the hippocampal slice preparation is sufficient to exert a tonic inhibitory influence on the amplitude of synaptic responses

4 Cyclic adenosine 3′,5′-monophosphate (cyclic AMP) and its dibutyryl derivative had depressant effects on the amplitude of field responses which were blocked by theophylline, suggesting that they are able to act at the extracellular adenosine receptor (-)-Isoprenaline (which raises tissue cyclic AMP levels), and the 8-p-chlorophenylthio derivative of cyclic AMP both increased the amplitude of population spike responses, and these effects were not blocked by theophylline, suggesting that the physiological effects of adenosine are not mediated via a cyclic AMP-dependent mechanism

5 Since adenosine is not the transmitter at this CA1 pyramidal cell synapse, but is apparently present in the extracellular compartment in sufficient concentrations to affect the synaptic physiology of this region, this provides strong evidence in favour of the concept of a neuromodulatory role for adenosine in the central nervous system

ADENINE NUCLEOTIDES AND SYNAPTIC TRANSMISSION IN THE in vitro RAT HIPPOCAMPUS

Differential rapid analysis of ascorbic acid and ascorbic acid 2-sulfate by dinitrophenylhydrazine method.

Effects of purine compounds on cholinergic nerves. Specificity of adenosine and related compounds on acetylcholine release in electrically stimulated guinea pig ileum

Fundamental studies on physiological and pharmacological actions of L-ascorbate 2-sulfate. V. On the hypolipidemic and antiatherosclerotic effects of L-ascorbate 2-sulfate in rabbits.

https://www.jstage.jst.go.jp/article/jphs1951/30/1/30_1_21/_pdf

Spasmogenic effects of l-ascorbic acid on the guinea pig isolated ileum preparation

The effects of L-ascorbate 2-sulfate (AAS) on the lipid metabolism were examined in Triton-induced hyperlipemic mice, hyper cholesterolemic and normal rats, the following results being obtained. 1) In Triton-induced hyperlipemic mice, AAS (300mg/kg) significantly decreased the serum cholesterol level, while L-ascorbate (AA, 175mg/kg) was found ineffective. 2) In hypercholesterolemic rats fed 0.5 % cholester ol diet, the consecutive administration of AAS decreased the level of serum cholesterol and liver triacylglycerols. AA only slightly affected these levels. However, both AAS and AA prevented the unordinal increase in the liver weight caused by cholesterol feeding. 3) In normal rats, the administration of AAS over a 4-week period decreased the level of serum cholesterol and liver triacylglycerols.

Eiichi Hayashi

Papers

Differential rapid analysis of ascorbic acid and ascorbic acid 2-sulfate by dinitrophenylhydrazine method.

Effects of purine compounds on cholinergic nerves. Specificity of adenosine and related compounds on acetylcholine release in electrically stimulated guinea pig ileum

Fundamental studies on physiological and pharmacological actions of L-ascorbate 2-sulfate. V. On the hypolipidemic and antiatherosclerotic effects of L-ascorbate 2-sulfate in rabbits.

Spasmogenic effects of l-ascorbic acid on the guinea pig isolated ileum preparation

Fundamental studies on physiological and pharmacological actions of l-ascorbate 2-sulfate. i. on the hypolipidemic effects